While statin therapy has effectively reduced cardiovascular events, data emerging in 2008 raised concerns regarding increased risk of new onset diabetes while on statins. Large studies and trials have since reiterated the same findings.¹ The recent study by Kokkinos et al. is one of the first studies aimed at assessing the impact of behavior modification, notably cardiorespiratory fitness, to attenuate the incidence of diabetes among statin users.

In this study, the investigators identified 4,092 individuals from a prospectively maintained data registry, comprising over 21,000 veterans from 1986 to 2014 with a documented dyslipidemia.¹ These veterans received statin therapy for at least six months in the absence of type 2 diabetes or ischemia on exercise tolerance testing. To serve as controls, 3,001 individuals were identified who were not treated with statins, had no prior history of diabetes and had a normal exercise test. The cohort was stratified into four cardiorespiratory fitness categories based on age-stratified quartiles of peak metabolic equivalents achieved: least-fit, low-fit, moderate-fit and high-fit. The primary endpoint was the development of type 2 diabetes at the end of the study period, determined from electronic medical records in accordance with the International Classification of Diseases, Ninth Revision.

Incidence of type 2 diabetes was 24% (HR 1.24; 95% CI 1.11-1.39, P < 0.001) among statin users compared with the non-statin users. Type 2 diabetes occurred in 1,075 statin-treated patients (26.3%) with an average incidence rate of 30.6 events per 1000 person-years. Further analysis revealed body mass index (HR 1.07; 95% CI, 1.05-1.08), hypertension (HR 1.49; 95% CI 1.66-2.14), smoking (HR 1.89; 95% CI, 1.66-2.14) and sleep apnea (HR 1.35; 95% CI, 1.15-1.59) were predictors of type 2 diabetes incidence. Moreover, the use of ACEI/ARBs, diuretics or beta blockers, medications thought to occasionally increase the incidence of diabetes, did not elevate the risk of diabetes significantly.

The relative risk of developing type 2 diabetes decreased with higher cardiorespiratory fitness compared with the least-fit group: low-fit (HR 0.82; 95% CI, 0.70-0.95), moderate-fit (HR 0.76; 95% CI, 0.65-0.90), high-fit (HR 0.66; 95% CI: 0.53-0.82). These findings extrapolated to a decrease in incidence of type 2 diabetes by 6% for every 1-metabolic increase in cardiorespiratory fitness (HR 0.94; 95% CI: 0.91-0.97). The investigators performed additional multivariable Cox proportional hazards, using the non-statin-treated cohort and compared the risk of developing diabetes in the statin-treated cohort. The incidence was higher among patients in the least-fit (HR 1.5; 95% CI, 1.30-1.73) and low-fit (HR 1.22; 95% CI, 1.06-1.41) groups; however, the risk was similar to those not treated with statins in the moderate- and high-fit patients.

Evidence from meta-analyses suggested an increased risk of diabetes at all doses of statins, with a greater risk at higher doses compared with lower doses. On March 1, 2012, the FDA introduced a warning on the risk of diabetes to the labels of statin agents. Similar concerns were raised by European drug authorities. These regulatory changes raised questions as to whether the cardiovascular benefits of treatment with statins exceeded risk of diabetes, especially in primary prevention where it is widely used. An analysis from the JUPITER (Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin) trial was designed to address this controversy.² Analysis of patients with at least one major risk factor for developing diabetes (metabolic syndrome, HbA1c > 6%, BMI 30kg/m² or greater, impaired fasting glucose) revealed a 28% increase in the risk of developing diabetes (HR: 1.28; 95%, CI 1.07-1.54) and a 39% reduction in cardiovascular risk. Patients without risk factors had a 52% reduction in cardiovascular risk with no increase in diabetes (HR: 0.99; 95% CI: 0.45-2.21). In a subgroup analysis limited to diabetics (HR: 1.25; 95% CI: 1.05-1.49), the point estimate of cardiovascular risk reduction with statin therapy was consistent with that for the trial (HR: 0.56; 95% CI: 0.46-0.69).

With regards to secondary CVD prevention, a large PCSK9 randomized controlled trial showed that reduction in LDL cholesterol by up to 60% did not significantly increase risk of new-onset diabetes within 2.2 years of follow-up.³ However, Ference et al. used a 'Mendelian randomization' approach to study the effect of LDL cholesterol lowering variants in PCSK9 and HMGCR on the risk of new onset diabetes and cardiovascular events.⁴ Genetic scores were devised to mimic the effects of statin and PCSK9 inhibitors. The scores were compared to assess the risk of diabetes and reduction in cardiovascular disease in order to determine its clinical safety. Interestingly, PCSK9 variants were associated with an 11.2% increase in the onset of diabetes (OR: 1.11; 95% CI: 1.04-1.19), similar to a 12.7% risk in HMGCR variants (OR: 1.13; 95% CI: 1.06-1.20). Both agents when used together had independent and additive effects on the risk of diabetes. The mechanism for this is largely unknown; however, the increased risk of diabetes in both variants was confined to patients with impaired fasting glucose and may involve an LDL-receptor mediated pathway. This is further supported by an observation that individuals with familial hypercholesterolemia have a lower prevalence of diabetes than unaffected relatives.⁵ The study showed that the corresponding reduction of cardiovascular risk far exceeded the risk of diabetes and decreased the risk of cardiovascular events in patients with and without diabetes among PCSK9 and HMGCR variants similarly. These results are similar to those from a meta-analysis that statins are associated with the same proportional reduction in the risk of cardiovascular events in both diabetics and non-diabetics.⁶

Diabetes affects 170 million people worldwide, including 20.4 million in the United States alone.⁷ Several studies have demonstrated an inverse relationship between reduced cardiorespiratory fitness and glucose intolerance, diabetes, metabolic syndromes and a direct relationship with insulin sensitivity and glucose disposal rate.^8,9 The Henry Ford Exercise Testing Project (FIT) was designed to identify the association of fitness with the incidence of diabetes in over 46,000 individuals.¹⁰ During the median follow up of 5.1 years, 14.6% off patients developed new-onset diabetes. After adjusting for demographic characteristics and diabetes-related risk factors, patients achieving >12 METS had a 54% lower risk of diabetes incidence compared with patients achieving <6 METS (HR: 0.46; 95% CI: 0.41-0.51). The association was greatest when a MET >8 was achieved. For every 1 MET increment, a relative risk reduction of 8%, 8%, and 6% was seen in the total cohort, non-statin group, and statin group respectively (p < 0.001). A meta-analysis on obesity and cardiovascular outcomes based Mendelian randomization showed a causal link between obesity and coronary artery disease, type 2 diabetes and heart failure.¹¹ These findings not only question the concept of 'obesity paradox' in those free of diabetes at baseline, but also emphasize that weight is independent and causative along the path towards diabetes.

Through their study, Kokkinos et al. have further established a strong correlation between statin use and the incidence of new onset diabetes. Prior studies have shown that the cardiovascular benefits of statin therapy exceed the risk of diabetes. However, this study is unique to demonstrate a decreased risk through higher fitness, adjusting for diabetes risk factors. The risk of developing diabetes decreased progressively with increased fitness. When comparison was made with non-statin users, the risk of developing diabetes remained significant only in the low fitness groups, including a 50% higher incidence in the least fit group. In fact, the cardiorespiratory fitness level to lower the risk of type 2 diabetes in the statin group was calculated as 8 metabolic equivalent which is achievable through moderate intensity exercise all age groups. Although the contribution of statins to the total incidence of diabetes is limited and outweighs cardiovascular benefits, widespread and increasing use of statins for primary prevention still adds to the burden of diabetes. The synergistic effects of statin therapy on cardiovascular effects, diabetes and cardiorespiratory fitness bring about an onus on healthcare providers to encourage moderate exercise in new and existing statin users, and subsequently attenuate its adverse effects.

References

1. Kokkinos P, Faselis C, Narayan P, et al. Cardiorespiratory fitness and incidence of type 2 diabetes in United States veterans on statin therapy. Am J Med 2017;130:1192-8.
2. Ridker PM, Pradhan A, MacFadyen JG, Libby P, Glynn RJ. Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: an analysis from the JUPITER trial. Lancet 2012;380:565-71.
3. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017;376:1713-22.
4. Ference BA, Robinson JG, Brook RD, et al. Variation in PCSK9 and HMGCR and risk of cardiovascular disease and diabetes. N Engl J Med 2016;375:2144-53.
5. Besseling J, Kastelein JJ, Defesche JC, Hutten BA, Hovingh GK. Association between familial hypercholesterolemia and prevalence of type 2 diabetes mellitus. JAMA 2015;313:1029-36.
6. Cholesterol Treatment Trialists' Collaborators, Kearney PM, Blackwell L, et al. Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet 2008;371:117-25.
7. Cowie CC, Rust KF, Byrd-Holt DD, et al. Prevalence of diabetes and high risk for diabetes using A1C criteria in the U.S. population in 1988-2006. Diabetes Care 2010;33:562-8.
8. Van Dam RM, Schuit AJ, Feskens EJ, Seidell JC, Kromhout D. Physical activity and glucose tolerance in elderly men: the Zutphen Elderly study. Med Sci Sports Exerc 2002;34:1132-6.
9. Williams PT. Changes in vigorous physical activity and incident diabetes in male runners. Diabetes Care 2007;30:2838-42.
10. Cardiorespiratory fitness and incident diabetes: the FIT (Henry Ford Exercise Testing) project. Diabetes Care 2015;28:1075-81.
11. Riaz H, Shah NP, Khan MS, Goyal A, Siddiqi TJ, Ahmed HM. Is obesity causally linked with cardiovascular outcomes? A meta-analysis of Mendelian randomization studies (to be presented at American College of Cardiology Scientific Sessions 2018).

Keywords: Body Mass Index, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Metabolic Syndrome, Metabolic Equivalent, Hyperlipoproteinemia Type II, Cholesterol, LDL, Risk Factors, Coronary Artery Disease, Glycated Hemoglobin A, Diabetes Mellitus, Type 2, Insulin Resistance, Glucose Intolerance, Cardiovascular Diseases, Diuretics, Glucose, Prevalence, Veterans, International Classification of Diseases, Obesity, Dyslipidemias, Receptors, LDL, Hypertension, Primary Prevention, Heart Failure, Sleep Apnea Syndromes, Behavior Therapy, Smoking, Registries, Health Personnel, Cohort Studies

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